Delineation of the signaling mechanisms that guide the differentiation and selection of germinal center B cells remains a challenging topic. From a genetic approach, the ability to selectively modify genes in germinal center B cells has only recently been achieved. Moreover, germinal center B cells represent a small and transient subset of B cells that are difficult to maintain or expand in vitro. Nonetheless, it is imperative o develop new approaches to study this subset as it is becoming clear that activation and differentiation characteristics of more abundant nave recirculating B cells are not representativ of the heterogeneous germinal center B cell compartment. Herein we will focus on the NIK/IKK1 axis, which we have found to be required for germinal center formation, but the downstream functional targets are unidentified. Here we will utilize cutting edge mass cytometry, imaging cytometry, specialized in vitro cultures and conditional gene targeting to dissect the individual and combined roles of NIK and IKK1 in germinal center B cell differentiation. These studies will provide novel insights into the signal transduction pathways accounting for the generation of high-affinity memory B cells and plasma cells, as well as a better understanding of how dysregulation of NIK/IKK1 signaling promotes multiple myeloma and lymphomagenesis

Public Health Relevance

The proposed studies will provide fundamental insight into the mechanisms that govern the germinal center B cell response, which accounts for the generation of high-affinity memory B cells and antibody-producing cells. In addition, they will inform on how dysregulated NIK/IKK1 activity contributes to myeloma and lymphoma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041649-16
Application #
9060895
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Ferguson, Stacy E
Project Start
1998-04-01
Project End
2020-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
16
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Sanford Burnham Prebys Medical Discovery Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Rickert, Robert C (2013) New insights into pre-BCR and BCR signalling with relevance to B cell malignancies. Nat Rev Immunol 13:578-91

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